Comparison Of Different Combination Strategies Of Targeted Drugs In The Treatment Of Recurrent Ovarian Cancer

Objective:Ovarian cancer(OC)has entered the era of targeted therapy,but there are still many clinical problems that are difficult to solve through randomized controlled clinical trials.At present,there is a lack of randomized controlled trials to directly compare the efficacy of polyadenosine diphosphate ribose polymerase(PARP)inhibitors,angiogenesis inhibitors(AIs)and chemotherapy(CT)in the treatment of recurrent ovarian cancer(ROC).Therefore,this paper compares the efficacy and safety of different combination strategies of targeted drugs in the treatment of ROC by Bayesian Network Meta analysis,which is of great significance for clinicians to choose the treatment plan of ROC.Methods:The English databases Pumbed,Web of Science,The Cochrane Library and EMBASE were searched by computer,and the English literatures from the establishment of the database to June 2022 were searched to determine the RCTs to evaluate the efficacy and safety of targeted drugs alone and their combination strategies in the treatment of ROC.The main outcome measures were progression-free survival(PFS),overall survival(OS),and adverse events of grade 3or above(AEs).The data analysis software uses Revman software 5.3 to strictly evaluate the quality of the final included literature according to the Cochrane risk bias assessment tool,and the R 4.2.1 software uses Markov chain Monte Carlo method for Bayesian network meta analysis.Results:Nineteen studies,all randomized controlled trials(RCTs),were included,including 6 treatment measures(PARPi,AT+CT,PARPi+AT,PARPi+CT,PARPi+BRCAm,CT),with a total of 5481 patients.The results of network meta analysis showed that:(1)in terms of PFS,AT+CT(HR=0.56,95%Cr I: 0.50～0.62),PARPi+AT(HR=0.74,95%Cr I: 0.56～0.95),PARPi+CT(HR=0.51,95%Cr I: 0.32～0.82)and PARPi+BRCAm(HR=0.67,95%Cr I:0.53～0.87)could significantly prolong PFS in patients with recurrent ovarian cancer compared with CT.Compared with single oral PARPi,the efficacy of AT+CT,PARPi+AT,PARPi+CT and PARPi+BRCAm was more significant,and the corresponding HR and 95%Cr I were 0.45(0.34,0.59),0.60(0.45,0.78),0.41(0.24,0.70),0.54(0.38,0.78),respectively.The efficacy of AT+CT was more significant than that of PARPi+AT(HR=0.76,95%Cr I: 0.57～1.0).The effect of PARPi+CT on prolonging the PFS of ROC patients is the most likely to rank first among the six treatment prescriptions,with a SUCRA value of 87.6%,followed by AT+CT(SUCRA=85.0%),PARPi+BRCAm(SUCRA=58.6%),PARPi+AT(SUCRA=48.3%),CT(SUCRA=19.5%)and PARPi(SUCRA=0.9%).(2)In terms of OS,AT+CT(HR=0.82,95%Cr I: 0.71～0.92)can significantly prolong the OS of patients with recurrent ovarian cancer compared with CT,and compared with PARPi+BRCAm,the curative effect of AT+CT is more significant.The corresponding HR and 95%Cr I are 0.69(0.52,0.91).The effect of AT+CT on prolonging OS in patients with ROC is the most likely to rank first among the six treatment schemes,with a SUCRA value of 89.2%,followed by PARPi+AT(SUCRA=76.4%),CT(SUCRA=51.8%),PARPi(SUCRA=32.3%),PARPi+CT(SUCRA=28.4%)and PARPi+BRCAm(SUCRA=21.8%).(3)In terms of PFS,AT+CT(HR=0.57,95%Cr I: 0.45～0.71),PARPi+CT(HR=0.51,95%Cr I: 0.28～0.94)and PARPi+BRCAm(HR=0.50,95%Cr I: 0.32～0.76)could significantly prolong the PFS of platinum-sensitive recurrent ovarian cancer patients compared with CT,and the efficacy of AT+CT,PARPi+AT,PARPi+CT and PARPi+BRCAm was more significant than that of oral PARPi alone.The corresponding HR and 95%Cr I were 0.46(0.29,0.73),0.58(0.37,0.84),0.41(0.20,0.87),0.40(0.22,0.73),respectively.The effect of PARPi+BRCAm on prolonging PFS in patients with PSOC is the most likely to rank first among the six treatment schemes,with a SUCRA value of 82.6%,followed by PARPi+CT(SUCRA=78.1%),AT+CT(SUCRA=69.4%),PARPi+AT(SUCRA=48.0%),CT(SUCRA=19.0%)and PARPi(SUCRA=2.9%).(4)In terms of OS,there was no significant difference among PARPi,AT+CT,PARPi+CT,PARPi+BRCAm and CT,suggesting that these five treatments may have no significant difference in the improvement of OS in patients with platinum-sensitive recurrent ovarian cancer.The effect of AT+CT on prolonging OS in patients with PSOC is the most likely to rank first among the five treatment schemes,with a SUCRA value of 84.2%,followed by CT(SUCRA=51.1%),PARPi(SUCRA=49.3%),PARPi+BRCAm(SUCRA=38.0%)and PARPi+CT(SUCRA=27.4%).(5)In terms of PFS,AT+CT(HR=0.54,95%Cr I: 0.42～0.67)could significantly prolong the PFS of patients with platinum-resistant recurrent ovarian cancer compared with CT,and AT+CT was more effective than oral PARPi alone.The corresponding HR and 95%Cr I were 0.49(0.24,0.93).The effect of AT+CT on prolonging PFS in patients with PROC is the most likely to rank first among the five treatment schemes,with a SUCRA value of 94.7%,followed by PARPi+AT(SUCRA=57.7%),PARPi+BRCAm(SUCRA=54.5%),CT(SUCRA=24.3%)and PARPi(SUCRA=18.7%).(6)In terms of OS,AT+CT(HR=0.72,95%Cr I: 0.54～0.92)could significantly prolong the OS of patients with platinum-resistant recurrent ovarian cancer compared with CT,and AT+CT was more effective than PARPi+BRCAm.The corresponding HR and 95%Cr I were 0.48(0.26,0.86).The effect of AT+CT on prolonging OS in patients with PROC is the most likely to rank first among the five treatment schemes,with a SUCRA value of 92.8%,followed by PARPi+AT(SUCRA=69.8%),CT(SUCRA=49.9%),PARPi(SUCRA=26.1%)and PARPi+BRCAm(SUCRA=11.3%).(7)In terms of PFS,the ratio of PARPi+CT(HR=0.21,95%Cr I: 0.048～0.91)to CT can significantly prolong the PFS of platinum-sensitive recurrent ovarian cancer patients with BRCA mutation.The effect of PARPi+CT on prolonging PFS in patients with platinum-sensitive recurrent ovarian cancer BRCA mutation was the most likely to rank first among the five treatment schemes,with a SUCRA value of 93.2%,followed by PARPi+AT(SUCRA=71.6%),PARPi(SUCRA=50.4%),CT(SUCRA=24.0%)and AT+CT(SUCRA=10.6%).(8)In terms of PFS,there was no significant difference among PARPi,AT+CT,PARPi+AT,PARPi+CT and CT,suggesting that these five treatments may have no significant difference in the improvement of PFS in platinum-sensitive recurrent ovarian cancer patients without BRCA.The effect of AT+CT on prolonging PFS in patients with platinum-sensitive ovarian cancer with non-BRCA mutation was the most likely to rank first among the five treatments,with a SUCRA value of 88.3%,followed by PARPi+CT(SUCRA=55.4%),PARPi+AT(SUCRA=55.3%),CT(SUCRA=39.3%)and PARPi(SUCRA=11.4%).(9)In terms of adverse events,there was no significant difference among PARPi,AT+CT,PARPi+AT,PARPi+CT and CT,suggesting that there was no significant difference in the probability of grade 3 and grade 4 adverse events among the five treatments.Among the five treatment schemes,the probability of grade 3 and grade 4adverse events in PARPi+AT patients is the most likely to rank first among the five treatment schemes,with a SUCRA value of 82.1%,followed by PARPi(SUCRA=51.9%),AT+CT(SUCRA=51.5%),PARPi+CT(SUCRA=45.6%)and CT(SUCRA=18.6%).Conclusion:AT+CT benefits significantly in terms of PFS and OS.Compared with chemotherapy alone,it can significantly improve the survival outcome of patients.In addition,the improvement of OS in patients with platinum-sensitive recurrence or platinum-resistant recurrence and non-BRCA mutation patients with platinum-sensitive recurrence ranked first,suggesting the efficacy of angiogenesis drugs combined with chemotherapy in the treatment of ROC.After maintenance therapy after PARPi combined with chemotherapy,the efficacy of PFS in patients with platinum-sensitive recurrent BRCA mutation may be the first;PARPi can be considered as the first choice for maintenance therapy in patients with platinum-sensitive recurrent BRCA mutation.Oral administration of PARPi alone may have the worst effect on posterior line therapy and is not recommended.Although there is no significant statistical difference in our study,we still believe that PARPi+AT has considerable potential and can be expected to be selectively used as a non-platinum drug in future clinical trials.